Characterization of torque-related activity in primary motor cortex during a multijoint postural task.

The present study examined neural activity in the shoulder/elbow region of primary motor cortex (M1) during a whole-limb postural task. By selectively imposing torques at the shoulder, elbow, or both joints we addressed how neurons represent changes in torque at a single joint, multiple joints, and their interrelation. We observed that similar proportions of neurons reflected changes in torque at the shoulder, elbow, and both joints and these neurons were highly intermingled across the cortical surface. Most torque-related neurons were reciprocally excited and inhibited (relative to their unloaded baseline activity) by opposing flexor and extensor torques at a single joint. Although coexcitation/coinhibition was occasionally observed at a single joint, it was rarely observed at both joints. A second analysis assessed the relationship between single-joint and multijoint activity. In contrast to our previous observations, we found that neither linear nor vector summation of single-joint activities could capture the breadth of neural responses to multijoint torques. Finally, we studied the neurons' directional tuning across all the torque conditions, i.e., in joint-torque space. Our population of M1 neurons exhibited a strong bimodal distribution of preferred-torque directions (PTDs) that was biased toward shoulder-extensor/elbow-flexor (whole-limb flexor) and shoulder-flexor/elbow-extensor (whole-limb extensor) torques. Notably, we recently observed a similar bimodal distribution of PTDs in a sample of proximal arm muscles. This observation illustrates the intimate relationship between M1 and the motor periphery.

Kinematics and kinetics of multijoint reaching in nonhuman primates.

The present study identifies the mechanics of planar reaching movements performed by monkeys (Macaca mulatta) wearing a robotic exoskeleton. This device maintained the limb in the horizontal plane such that hand motion was generated only by flexor and extensor motions at the shoulder and elbow. The study describes the kinematic and kinetic features of the shoulder, elbow, and hand during reaching movements from a central target to peripheral targets located on the circumference of a circle: the center-out task. While subjects made reaching movements with relatively straight smooth hand paths and little variation in peak hand velocity, there were large variations in joint motion, torque, and power for movements in different spatial directions. Unlike single-joint movements, joint kinematics and kinetics were not tightly coupled for these multijoint movements. For most movements, power generation was predominantly generated at only one of the two joints. The present analysis illustrates the complexities inherent in multijoint movements and forms the basis for understanding strategies used by the motor system to control reaching movements and for interpreting the response of neurons in different brain regions during this task.

Neural activity in primary motor cortex related to mechanical loads applied to the shoulder and elbow during a postural task.

Whole-arm motor tasks performed by nonhuman primates have become a popular paradigm to examine neural activity during motor action, but such studies have traditionally related cell discharge to hand-based variables. We have developed a new robotic device that allows the mechanics of the shoulder and elbow joints to be manipulated independently. This device was used in the present study to examine neural activity in primary motor cortex (MI) in monkeys (Macaca mulatta) actively maintaining their hand at a central target as they compensated for loads applied to the shoulder and/or elbow. Roughly equal numbers of neurons were sensitive to mechanical loads only at the shoulder, only at the elbow, or loads at both joints. Neurons possessed two important properties. First, cell activity during multi-joint loads could be predicted from its activity during single-joint loads as a vector sum in a space defined by orthogonal axes for the shoulder and elbow. Second, most neurons were related to flexor torque at one joint coupled with extensor torque at the other, a distribution that paralleled the observed activity of forelimb muscles. These results illustrate that while MI activity may be described by independent axes representing each mechanical degree-of-freedom, neural activity is also strongly influenced by the specific motor patterns used to perform a given task.

Dissociation between hand motion and population vectors from neural activity in motor cortex.

The population vector hypothesis was introduced almost twenty years ago to illustrate that a population vector constructed from neural activity in primary motor cortex (MI) of non-human primates could predict the direction of hand movement during reaching. Alternative explanations for this population signal have been suggested but could not be tested experimentally owing to movement complexity in the standard reaching model. We re-examined this issue by recording the activity of neurons in contralateral MI of monkeys while they made reaching movements with their right arms oriented in the horizontal plane-where the mechanics of limb motion are measurable and anisotropic. Here we found systematic biases between the population vector and the direction of hand movement. These errors were attributed to a non-uniform distribution of preferred directions of neurons and the non-uniformity covaried with peak joint power at the shoulder and elbow. These observations contradict the population vector hypothesis and show that non-human primates are capable of generating reaching movements to spatial targets even though population vectors based on MI activity do not point in the direction of hand motion.

Control of saccade initiation in a countermanding task using visual and auditory stop signals.

We examined inhibitory control in an oculomotor countermanding task, where the primary task required a saccadic eye movement be made to a target and a less-frequent secondary task required that the movement be halted. Previous studies have used a visual stimulus presented centrally on the fovea as the signal to stop or countermand a saccade. In these previous studies, there are at least two possible sources of saccadic inhibition: (1) sensory stimulation at the fovea can elicit a bottom-up mechanism, where a visual transient signal can delay or inhibit the developing saccade command; and (2) information based on the task instruction can be used to initiate a top-down mechanism to halt the movement. In the present study, we used both visual and auditory stop signals to test the hypothesis that the bottom-up mechanism is activated only after presentation of a foveal visual stop signal. Subjects were instructed first to look at a central spot and then to look to an eccentric visual target that appeared randomly to the left or right of center. On about one-third of the trials, a stop signal was presented. Three types of stop signals were used with equal probability: a broad-band noise burst (auditory), a central fixation spot (visual), and a combination of the auditory and visual stimuli (combined). Saccadic reaction time and stop-signal accuracy were used to calculate stop signal reaction time (SSRT), an estimate of the time required to inhibit the eye movement. Mean SSRT was longer for the auditory stop signals (201 ms) than for the signals with a foveal visual component (visual 113 ms; combined 91 ms). We conclude that a foveal visual stop signal in an oculomotor countermanding task changes the measure of inhibitory control to reflect not only inhibitory processes but also the sensory information afforded by stimulation at the fovea.

Structurally homogeneous and heterogeneous synthetic combinatorial libraries.

We have designed and synthesized structurally homogeneous and heterogeneous nonpeptide libraries. Structurally homogeneous libraries are characterized by the presence of one common structural unit, a scaffold, in all library compounds (e.g. cyclopentane, cyclohexane, diketopiperazine, thiazolidine). In structurally heterogeneous libraries different organic reactions (acylation, etherification, reductive amination, nucleophilic displacement) were applied to connect bifunctional building blocks unrelated in structure (aromatic hydroxy acids, aromatic hydroxy aldehydes, amino alcohols, diamines, and amino acids). The focus of this communication is to document the use of bifunctional building blocks for the design and synthesis of structurally heterogeneous libraries of N-(alkoxy acyl)amino acids, N,N'-bis-(alkoxy acyl)diamino acids, N-acylamino ethers, N-(alkoxy acyl)amino alcohols, N-alkylamino ethers, and N-(alkoxy aryl)diamines.

MARS--multiple automated robotic synthesizer for continuous flow of peptides.

We have designed and constructed a multiple automated robotic synthesizer, the MARS. Its novel timing procedure for handling multiple synthetic tasks eliminates unnecessary respite time by keeping the robotic arm in continuous operation. Polypropylene syringes equipped at the bottom with polypropylene frits serve as physically independent reaction vessels. All operations are performed by the robotic arm, which is equipped with a specially designed gripper to hold a syringe and to aspirate and dispense liquid. Typically, the MARS synthesizes concurrently 5 to 15 peptides of different length, and once one peptide is finished it automatically starts the synthesis of the next peptide in the queue, assuring a continuous flow of peptides.

Linear presentation of variable side-chain spacing in a highly diverse combinatorial library.

A synthetic library that presents potential pharmacophores in a linear fashion with variable spacing was designed (alpha, beta, gamma-library). To prove the concept, we synthesized a number of individual compounds as well as a model library. Diamino acids connected by amide bonds via their alpha- or side-chain amino groups were used to form the backbone (scaffold) of this library. The remaining amino group of the diamino acids were acylated by a variety of carboxylic acids, generating an appreciable diversity of compounds in this library. The compositions of compounds in the library were identified by reading a peptide tag synthesized concurrently with the library structures. This code contained the information regarding the carboxylic acid coupled, and the diamino acid and amino group to which the acid was coupled.